ES2198196A1 - Topical compositions comprising an opioid analgesic and an nmda antagonist - Google Patents
Topical compositions comprising an opioid analgesic and an nmda antagonistInfo
- Publication number
- ES2198196A1 ES2198196A1 ES200150003A ES200150003A ES2198196A1 ES 2198196 A1 ES2198196 A1 ES 2198196A1 ES 200150003 A ES200150003 A ES 200150003A ES 200150003 A ES200150003 A ES 200150003A ES 2198196 A1 ES2198196 A1 ES 2198196A1
- Authority
- ES
- Spain
- Prior art keywords
- morphine
- topical
- tolerance
- nmda
- peripheral
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 230000000699 topical effect Effects 0.000 title abstract 7
- 239000003703 n methyl dextro aspartic acid receptor blocking agent Substances 0.000 title abstract 2
- 239000000203 mixture Substances 0.000 title 1
- 239000000014 opioid analgesic Substances 0.000 title 1
- BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical compound O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 abstract 16
- 229960005181 morphine Drugs 0.000 abstract 8
- HOKKHZGPKSLGJE-GSVOUGTGSA-N N-Methyl-D-aspartic acid Chemical compound CN[C@@H](C(O)=O)CC(O)=O HOKKHZGPKSLGJE-GSVOUGTGSA-N 0.000 abstract 3
- 230000002093 peripheral effect Effects 0.000 abstract 3
- HPZJMUBDEAMBFI-WTNAPCKOSA-N (D-Ala(2)-mephe(4)-gly-ol(5))enkephalin Chemical compound C([C@H](N)C(=O)N[C@H](C)C(=O)NCC(=O)N(C)[C@@H](CC=1C=CC=CC=1)C(=O)NCCO)C1=CC=C(O)C=C1 HPZJMUBDEAMBFI-WTNAPCKOSA-N 0.000 abstract 2
- 108700022183 Ala(2)-MePhe(4)-Gly(5)- Enkephalin Proteins 0.000 abstract 2
- 108010092674 Enkephalins Proteins 0.000 abstract 2
- URLZCHNOLZSCCA-VABKMULXSA-N Leu-enkephalin Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(O)=O)NC(=O)CNC(=O)CNC(=O)[C@@H](N)CC=1C=CC(O)=CC=1)C1=CC=CC=C1 URLZCHNOLZSCCA-VABKMULXSA-N 0.000 abstract 2
- 230000036592 analgesia Effects 0.000 abstract 2
- 230000000202 analgesic effect Effects 0.000 abstract 2
- 239000005557 antagonist Substances 0.000 abstract 2
- YQEZLKZALYSWHR-UHFFFAOYSA-N Ketamine Chemical compound C=1C=CC=C(Cl)C=1C1(NC)CCCCC1=O YQEZLKZALYSWHR-UHFFFAOYSA-N 0.000 abstract 1
- 102000004868 N-Methyl-D-Aspartate Receptors Human genes 0.000 abstract 1
- 108090001041 N-Methyl-D-Aspartate Receptors Proteins 0.000 abstract 1
- 229940127523 NMDA Receptor Antagonists Drugs 0.000 abstract 1
- 229940099433 NMDA receptor antagonist Drugs 0.000 abstract 1
- 102000003840 Opioid Receptors Human genes 0.000 abstract 1
- 108090000137 Opioid Receptors Proteins 0.000 abstract 1
- -1 [D-Ala2 Chemical compound 0.000 abstract 1
- 238000003556 assay Methods 0.000 abstract 1
- 239000003795 chemical substances by application Substances 0.000 abstract 1
- 231100000673 dose–response relationship Toxicity 0.000 abstract 1
- 229940079593 drug Drugs 0.000 abstract 1
- 239000003814 drug Substances 0.000 abstract 1
- 230000000694 effects Effects 0.000 abstract 1
- 230000001939 inductive effect Effects 0.000 abstract 1
- 229960003299 ketamine Drugs 0.000 abstract 1
- 230000007246 mechanism Effects 0.000 abstract 1
- 229940005483 opioid analgesics Drugs 0.000 abstract 1
- 230000003389 potentiating effect Effects 0.000 abstract 1
- 108090000765 processed proteins & peptides Proteins 0.000 abstract 1
- 102000004196 processed proteins & peptides Human genes 0.000 abstract 1
- 102000005962 receptors Human genes 0.000 abstract 1
- 108020003175 receptors Proteins 0.000 abstract 1
- 230000009885 systemic effect Effects 0.000 abstract 1
- 231100000936 topical exposure Toxicity 0.000 abstract 1
- 239000012049 topical pharmaceutical composition Substances 0.000 abstract 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4468—Non condensed piperidines, e.g. piperocaine having a nitrogen directly attached in position 4, e.g. clebopride, fentanyl
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/33—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans derived from pro-opiomelanocortin, pro-enkephalin or pro-dynorphin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/485—Morphinan derivatives, e.g. morphine, codeine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P23/00—Anaesthetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P23/00—Anaesthetics
- A61P23/02—Local anaesthetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Gastroenterology & Hepatology (AREA)
- Immunology (AREA)
- Zoology (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Anesthesiology (AREA)
- Emergency Medicine (AREA)
- Pain & Pain Management (AREA)
- Neurosurgery (AREA)
- Biomedical Technology (AREA)
- Rheumatology (AREA)
- Neurology (AREA)
- Medicinal Preparation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
A topical opioid paradigm was developed to determine analgesic peripheral effects of morphine. Topical morphine as well as peptides such as [D-Ala2,MePhe4,Gly(ol)5]enkephalin (DAMGO) produced a potent, dose-dependent analgesia using the radiant heat tailflick assay. The topical drugs potentiated systemic agents, similar to the previously established synergy between peripheral and central sites of action. Local tolerance was rapidly produced by repeated daily topical exposure to morphine. Topical morphine tolerance was effectively blocked by the N-Methyl-D-Aspartate (NMDA) receptors antagonist MK801 and ketamine given either systemically or topically. NMDA receptor antagonists reversed pre-existing morphine tolerance. The activity of topical NMDA antagonists to block local morphine tolerance suggests that peripheral NMDA receptors mediate topical morphine tolerance. Morphine was cross tolerant to [D-Ala2,MePhe4,Gly(ol)5]enkephalin (DAMGO), but not to morphine-6 beta -glucuronide, implying different mechanisms of action. These observations have great importance in the design and use of opioids clinically. Topical pharmaceutical compositions comprising an analgesic that functions through an opiate receptor and an NMDA receptor antagonist for producing analgesia without inducing tolerance are described.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US9298298P | 1998-07-16 | 1998-07-16 | |
| US60/092982 | 1998-07-16 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| ES2198196A1 true ES2198196A1 (en) | 2004-01-16 |
| ES2198196B2 ES2198196B2 (en) | 2006-04-01 |
Family
ID=22236108
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| ES200150003A Expired - Fee Related ES2198196B2 (en) | 1998-07-16 | 1999-07-15 | TOPICAL COMPOSITIONS THAT INCLUDE AN OPIOID ANALGESIC AND AN NMDA ANTAGONIST. |
Country Status (15)
| Country | Link |
|---|---|
| US (1) | US7700122B1 (en) |
| EP (1) | EP1102589B1 (en) |
| JP (2) | JP2002520363A (en) |
| KR (1) | KR100762018B1 (en) |
| CN (1) | CN1309562A (en) |
| AT (1) | ATE344035T1 (en) |
| AU (1) | AU758448B2 (en) |
| BR (1) | BR9912827A (en) |
| CA (1) | CA2336902C (en) |
| DE (1) | DE69933874T2 (en) |
| DK (1) | DK1102589T3 (en) |
| ES (1) | ES2198196B2 (en) |
| IL (2) | IL140834A0 (en) |
| PT (1) | PT1102589E (en) |
| WO (1) | WO2000003716A1 (en) |
Families Citing this family (25)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| BR9912827A (en) | 1998-07-16 | 2001-05-02 | Sloan Kettering Inst Cancer | Topical compositions comprising an opioid analgesic and an nmda antagonist |
| ATE361667T1 (en) | 1999-03-23 | 2007-06-15 | Hibernation Therapeutics Ltd | STOPPING, PROTECTING AND PRESERVING ORGANS |
| US6455066B1 (en) * | 2000-03-10 | 2002-09-24 | Epicept Corporation | Intradermal-penetration agents for topical local anesthetic administration |
| AU2001257326A1 (en) | 2000-04-28 | 2001-11-12 | Memorial Sloan-Kettering Cancer Center | Topical anesthetic/opioid formulations and uses thereof |
| DE10025946A1 (en) * | 2000-05-26 | 2001-11-29 | Gruenenthal Gmbh | drug combination |
| US20020013331A1 (en) | 2000-06-26 | 2002-01-31 | Williams Robert O. | Methods and compositions for treating pain of the mucous membrane |
| US7820688B2 (en) | 2001-04-27 | 2010-10-26 | Memorial Sloan-Kettering Cancer Center | Topical anesthetic/opioid formulations and uses thereof |
| DE60143671D1 (en) | 2001-06-07 | 2011-01-27 | Sang Christine | TREATMENT OF NEUROPATHIC PAIN BY N-METHYL-D-ASPARTATE (NMDA) RECEPTOR ANTAGONISTS |
| DE10141650C1 (en) | 2001-08-24 | 2002-11-28 | Lohmann Therapie Syst Lts | Safe transdermal therapeutic system for administration of fentanyl or analogous analgesics, having matrix layer of carboxy group-free polyacrylate adhesive providing high permeation rate |
| CN1691936A (en) * | 2002-09-09 | 2005-11-02 | 恩多制药公司 | Combined immediate release and extended release analgesic composition |
| WO2004056180A1 (en) * | 2002-12-23 | 2004-07-08 | Global Cardiac Solutions Pty Ltd | Organ preconditioning, arrest, protection, preservation and recovery (1) |
| DE10340428B4 (en) * | 2003-09-02 | 2015-02-12 | Acino Ag | Opioides analgesic containing transdermal formulation |
| EP1789028A2 (en) * | 2004-08-24 | 2007-05-30 | Neuromolecular Pharmaceuticals Inc | Compositions for treating nociceptive pain |
| AU2006345361B2 (en) | 2006-05-29 | 2014-04-10 | Hibernation Therapeutics, A Kf Llc | Improved tissue maintenance |
| US20090324748A1 (en) | 2006-07-25 | 2009-12-31 | Hibernation Therapeutics Limited | Trauma therapy |
| EP2173353B1 (en) | 2007-03-02 | 2015-05-06 | Hibernation Therapeutics, a KF LLC | Composition including Adenosine and Lignocaine |
| CN101317844B (en) * | 2007-06-08 | 2010-11-17 | 章劲夫 | Application of N-methyl-D-asparagic acid acceptor inhibitor in preparing contraceptive medicament |
| TWI380992B (en) | 2010-03-11 | 2013-01-01 | Univ Ishou | A small interfering rna for gene knockdown of the n-methyl-d-aspartate receptor nr1 subunit, it's application on reducing the n-methyl-d-aspartate receptor nr1 subunit in skin, it's use and a medication to release skin inflammation pain |
| CA2796774C (en) * | 2010-06-15 | 2020-06-02 | Gruenenthal Gmbh | Pharmaceutical combination for the treatment of pain |
| DE102010024105A1 (en) | 2010-06-17 | 2011-12-22 | Grünenthal GmbH | Transdermal administration of memantine |
| TWI417109B (en) | 2010-12-30 | 2013-12-01 | Univ Ishou | A short hairpin rna for gene knockdown of the n-methyl-d-aspartate receptor nr1 subunit, an use of a short hairpin rna in manufacturing a reagent foe gene knockdown of the n-methyl-d-aspartate receptor nr1 subunit and a medication to release skin inflamm |
| FR2998892B1 (en) | 2012-12-04 | 2015-01-02 | Pf Medicament | AMINOCYCLOBUTANE DERIVATIVES, PROCESS FOR PREPARING THEM AND THEIR USE AS MEDICAMENTS |
| BR112016000898A2 (en) | 2013-07-17 | 2017-08-22 | Hibernation Therapeuitics A Kf Llc | METHOD FOR STOPPING, PROTECTING AND PRESERVING AN ORGAN AND REDUCING TISSUE INJURY |
| CN107028968B (en) * | 2016-02-03 | 2020-12-04 | 江苏恒瑞医药股份有限公司 | A pharmaceutical composition containing morphine glucuronide or its pharmaceutically acceptable salt |
| CN114642744B (en) * | 2022-02-09 | 2023-05-23 | 南京医科大学 | Method for screening morphine-tolerance-relieving drugs |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1997010815A1 (en) * | 1995-09-22 | 1997-03-27 | Frome Bruce M | The preparation of topical regional compositions for the relief of pain |
| US5635204A (en) * | 1994-03-04 | 1997-06-03 | Montefiore Medical Center | Method for transdermal induction of anesthesia, analgesia or sedation |
| WO1998031358A1 (en) * | 1997-01-22 | 1998-07-23 | Cornell Research Foundation, Inc. | d-METHADONE, A NONOPIOID ANALGESIC |
Family Cites Families (15)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5322683A (en) * | 1989-05-01 | 1994-06-21 | Leonard Mackles | Anhydrous aerosol foam |
| JP2669951B2 (en) * | 1991-03-28 | 1997-10-29 | 雍憲 森本 | Transdermal composition containing narcotic analgesic |
| JPH0733681A (en) * | 1993-05-18 | 1995-02-03 | Sekisui Chem Co Ltd | Percutaneous patch |
| US5589480A (en) * | 1994-08-17 | 1996-12-31 | Elkhoury; George F. | Topical application of opioid analgesic drugs such as morphine |
| EP0808153B1 (en) * | 1995-02-10 | 1999-08-04 | Medtronic, Inc. | Method and device for administering analgesics |
| US5840731A (en) * | 1995-08-02 | 1998-11-24 | Virginia Commonwealth University | Pain-alleviating drug composition and method for alleviating pain |
| US5849761A (en) * | 1995-09-12 | 1998-12-15 | Regents Of The University Of California | Peripherally active anti-hyperalgesic opiates |
| AUPN605795A0 (en) * | 1995-10-19 | 1995-11-09 | F.H. Faulding & Co. Limited | Analgesic pharmaceutical composition |
| JPH09143061A (en) * | 1995-11-20 | 1997-06-03 | Showa Denko Kk | Percutaneous absorption preparation for analgesic |
| US5891885A (en) * | 1996-10-09 | 1999-04-06 | Algos Pharmaceutical Corporation | Method for treating migraine |
| WO1998016197A1 (en) * | 1996-10-15 | 1998-04-23 | Needham Charles W | Surgical method and composition therefor |
| DK0946157T3 (en) | 1996-12-16 | 2002-07-08 | Alcon Lab Inc | Topical use of kappa-opioid agonists for the treatment of eye pain |
| BR9912827A (en) | 1998-07-16 | 2001-05-02 | Sloan Kettering Inst Cancer | Topical compositions comprising an opioid analgesic and an nmda antagonist |
| JP2000169378A (en) | 1998-12-10 | 2000-06-20 | Taisho Pharmaceut Co Ltd | Composition for pharyngopathy |
| AU2001257326A1 (en) * | 2000-04-28 | 2001-11-12 | Memorial Sloan-Kettering Cancer Center | Topical anesthetic/opioid formulations and uses thereof |
-
1999
- 1999-07-15 BR BR9912827-6A patent/BR9912827A/en not_active IP Right Cessation
- 1999-07-15 ES ES200150003A patent/ES2198196B2/en not_active Expired - Fee Related
- 1999-07-15 AU AU49987/99A patent/AU758448B2/en not_active Ceased
- 1999-07-15 PT PT99934071T patent/PT1102589E/en unknown
- 1999-07-15 JP JP2000559851A patent/JP2002520363A/en active Pending
- 1999-07-15 US US09/806,645 patent/US7700122B1/en not_active Expired - Fee Related
- 1999-07-15 IL IL14083499A patent/IL140834A0/en active IP Right Grant
- 1999-07-15 KR KR1020017000660A patent/KR100762018B1/en not_active IP Right Cessation
- 1999-07-15 EP EP99934071A patent/EP1102589B1/en not_active Expired - Lifetime
- 1999-07-15 CA CA002336902A patent/CA2336902C/en not_active Expired - Fee Related
- 1999-07-15 AT AT99934071T patent/ATE344035T1/en not_active IP Right Cessation
- 1999-07-15 CN CN99808693A patent/CN1309562A/en active Pending
- 1999-07-15 WO PCT/US1999/016049 patent/WO2000003716A1/en active IP Right Grant
- 1999-07-15 DE DE69933874T patent/DE69933874T2/en not_active Expired - Fee Related
- 1999-07-15 DK DK99934071T patent/DK1102589T3/en active
-
2001
- 2001-01-10 IL IL140834A patent/IL140834A/en not_active IP Right Cessation
-
2007
- 2007-07-02 JP JP2007174667A patent/JP2007246546A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5635204A (en) * | 1994-03-04 | 1997-06-03 | Montefiore Medical Center | Method for transdermal induction of anesthesia, analgesia or sedation |
| WO1997010815A1 (en) * | 1995-09-22 | 1997-03-27 | Frome Bruce M | The preparation of topical regional compositions for the relief of pain |
| WO1998031358A1 (en) * | 1997-01-22 | 1998-07-23 | Cornell Research Foundation, Inc. | d-METHADONE, A NONOPIOID ANALGESIC |
Non-Patent Citations (2)
| Title |
|---|
| KOLESNIKOV, Y.A. et al.: Peripheral blockade of topical morphine tolerance by Ketamine. European J. of Pharmacol., 1999, Vol. 374, R1-R2, todo el documento. * |
| KOLESNIKOV, Y.A. et al.: Topical opioids in mice: analgesia and reversal of tolerance by a topical N-methyl D-Aspartate antagonist. J. Pharmacol. and Experimental Therap., 1999, Vol. 290, Nº 1, paginas 247-252, todo el documento. * |
Also Published As
| Publication number | Publication date |
|---|---|
| IL140834A0 (en) | 2002-02-10 |
| PT1102589E (en) | 2006-12-29 |
| WO2000003716A1 (en) | 2000-01-27 |
| ES2198196B2 (en) | 2006-04-01 |
| US7700122B1 (en) | 2010-04-20 |
| AU4998799A (en) | 2000-02-07 |
| DK1102589T3 (en) | 2006-12-04 |
| KR100762018B1 (en) | 2007-10-04 |
| EP1102589B1 (en) | 2006-11-02 |
| ATE344035T1 (en) | 2006-11-15 |
| KR20010070969A (en) | 2001-07-28 |
| IL140834A (en) | 2009-02-11 |
| CN1309562A (en) | 2001-08-22 |
| AU758448B2 (en) | 2003-03-20 |
| DE69933874T2 (en) | 2007-10-04 |
| CA2336902A1 (en) | 2000-01-27 |
| BR9912827A (en) | 2001-05-02 |
| CA2336902C (en) | 2009-04-21 |
| JP2007246546A (en) | 2007-09-27 |
| JP2002520363A (en) | 2002-07-09 |
| DE69933874D1 (en) | 2006-12-14 |
| EP1102589A1 (en) | 2001-05-30 |
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